Method of preparing quaternary salts of amino carbinols



' which is inexpensive and corresponds p-toluene sulfonic acid.

No Drawing. ApplicationJuly'27, 1954' -I Serial No. 446,167 i v ZClaims. (Cl.260326.5)

This invention relates to a novel method for thepreparation of amino carbinol quaternary salts of Formula I. Compounds of this type have been found to possess valuable .spasmolytic properties as inhibitors of the action of acetylcholine and particularly in ulcer treatment, The preparations previously known suffer, however, from various drawbacks. In some methods yields arepoor andin others the final products are; contarninated by impurities diflicult'to remove; The present inventionis concerned with a line of synthesis unenclimber-ed with these disadvantages; The starting matreial for our process is a cycloalkylphe'riylfketone (II) which'may be prepared in various ways'as by a Friedel-Crafts reaction of hexahydrobenzoyl chloride on benzene or of benzoyl chloride on cyclohexene (followed by dehalogenation).

hydroxyester III. While this ester might be expected tobe extremely subjectto dehydration, it is nevertheless possible by suitable procedures to isolate it over 80% in quantitative yield by lithium, aluminum hydride.

This keton'e is then subjected to a Reformatsky reaction 'to give the with sodium borohydride and catalytic reduction under high pressure and at an elevated temperature.

cycloalk I The glycol IV is then ester (V) by a hydrocarbyl' sulfonyl halide. The identity of the sulfonyl halide is not critical, p-toluene sulfonyl chloride, p-bromobenzene sulfonyl chloride, benzene sulfonyl chloride, ethane sulfonyl chloride-or methane sulfonyl chloride all suflice.- In general, none of these otters marked advantage over p-toluene sulfonyl chloride 0H mm-o-omomosom cycloalk i A converted to a monos'u lfoiiic'i to the non-toxic 7 p Similarly the sulfonate esters V can be reacted 2,842,555. Iatented July By employing only one equivalent of sulfonyl chloride under mild conditions, the primary alkyl group is unambiguously esterified.

The sulfonic ester, V, is. then allowed to react with a tertiary amine, affording the quaternary saltI. a

In the preparation of the'sulfonic ester V loss may ensue through a side reaction. If after'the main reaction is completed, pyridine hydrochloride ester, III to an amide. This is accomplished conveniently by dissolving it in methanol containing a primary amine, RNH In this reaction, a catalytic quantity of sodium methoxide is useful, though not essential.

The amide, VI, is then reduced with lithium aluminum hydride to the secondary amine, VII

0H otnr-o-ornonmnn cycloalk VII JV Vhen the secondaryamine, VII, is allowed to reactwith a. difunctional alkylating agent X-(CH ),,X'

WhereinX represents ;an,active alkylating functionsuch as tetramethylene bromide, pentamethylene bromide or a bis hydrocarbylsulfonate of tetramethylene or pentamethylene glycol in the presence of an acid-binding re-,

agent (such as sodium carbonate) a double alkylation occurs to form the quaternary salt Ia.

Alternatively the secondary amine may be reacted with a compound X--(CH ),,Y wherein Y is a group (e. g. OH) convertible into X such a case there is first formed,

a R CaHs-C-CHIC HgN-(CHg) "Y cycloalk (X being as before). In

' VIII.

to the quaternary salt Ia.

Still another application proceeds from the situation in which R in VII is H. .The operations described above through X(CH ),,X then yield a cyclic tertiary amine 3 secondary amines, "especially piperidine and pyrrolidine whereby also the tertiary amines VIII are formed.

EXAMPLE 1 Ethyl fkphenyl-B-cyclohexyl-B-hydroxy propionate In a carefully dried 1 liter 3 necked flask with stirrer condenser and dropping funnel was put 39.2 g. of 20 mesh granulated zinc which had been treated with HBr and then washed with 'water, ethanol'and acetone and dried at 55. It was covered with 5.0 ml. of dry benzene. 1

A solution of 93.5 g. of phenyl cyclohexyl ketone and 100 g. of freshly distilled ethyl bromoacetate in 250 ml. of dry benzene was prepared. About 50 ml. of this mix-- ture was added to the zinc. The mixture was stirred rapidly and heated to reflux. When a reaction started, the rest of the solution was added at a rate sufiicient to maintain gentle refluxing. The'total addition time-was onehalf'hour. The reactants were refluxed two hours more, cooled to room temperature and treated with 131 g. .of ammonium chloride in a saturated solution in water. The benzene layer was separated and the aqueous layer was extracted two times with benzene. The combined benzene extracts were washed with saturated aqueous ammonium chloride solution, then with 5% aqueous sodium bicarbonate solution, and then dried over magnesium sulfate. After the removal of the drying agent 'by filtration, the benzene was distilled to yield 156.5 g. of a light brown crystalline residue melting at 52-55 This was dissolved in 600 cc. of 95% ethanol and treated with crop of 6.1 g. could be obtained from the mother liquors.

EXAMPLE 2 I 1 -phenyl-1-cycl0hexyl-1,3-pr0parzedi0l In a 3 necked, 1 liter,.flask equipped with an eflieient stirrer, a water-cooled condenser protected from atmospheric moisture by a calcium chloride tube, and a dropping funnel was placed 5.7 g. of lithium aluminum hyd'ride and 200 ml. of anhydrous ethyl ether. The mixture was stirred and 27.5 g. of ethyl B-phenyl-fi-hydroxy-B cyclohexylpropionate'dissolved in 150 ml. of anhydrous ethyl ether was added during 45 minutes. The rate of addition'was suflicient to cause gentle refluxing of the ether. After this time, ml. of water was added cauti ously, then g. ofconcentrated sulfuric acid dissolved in 200 ml. of water. The reaction mixture separated into two layers, the lower of which was separated and ex: tracted with ether. This and the initial ether layer were combined and washed acid-free with sodium bicarbonate solution, and then washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an oil which solidified on standing or seeding. with a previously preparedcrystal, to give 23.1 g.-

of'a white crystalline solid, which was essentially analytically pure, but could be recrystallized from low-boiling.

petroleum ether fractions. A recrystallized sample melted at about 94 C. EXAMPLE 3 T he conversion of I-phenyl-1-cycl0hexyl-1,3-pr0panedi0l via 1-pheny3l-l-cyclohexyl-3-chloropropanolto N-(3- phenyl 3 cyclohexyl 3 hydroxypropyl) N-methylpyrrolidinium chloride A mixture of 10.25 g. of 1-phenyl-1-cyclohexyl-1',3- propanediol, 815 g. of p-toluenesulfonyl chloride, 3.75 g. of pyridine and 100 ml. of dry benzene was heated under reflux for seven hours, and let stand overnight protected by a calcium chloride tube. Some pyridine p-toluenesulfonate crystallized from the mixture, and was discarded (M. P. 117-119). To the solution were added 4.3 g,

A of pyridine hydrochloride and 10 ml. of pyridine, and the mixture was again heated under reflux for '18 hours. The resulting solution of the desired chlorohydroxy compound, pyridine, pyridine p-toluenesulfonate and pyridine hydrochloride was partitioned between benzene and dilute aqueous hydrochloric acid, and the benzene extracts wereheated on steam ,in vacuo to remove the solvent to leave 10.4 g. of an oil. This was transferred to a bottle and 50 ml. of benzene, 100 mg. of phenol,

and "8.5'g. of-"N-methylpyrrolidine were added. The

bottle" was heated in a steam bath for eight days. A lower layer separated during this time which crystallized on cooling to give 10.6 g. of N-(3-phenyl-3-cyclohexyl-3- hydroxynropyl)-N-methylpyrrolidinium chloride which had the same melting point alone and admixed with an authentic sample of this quaternary compound prepared by an alternativ'route, and essentially the same antispasmcdic activity on the isolated guinea pig gut as did the known sample.

7 EXAMPLE 4 r I-phenyl-1-cycl0hexylpr0pane-1-0l-3-p-t0luenesulf0nate A stirred solution of 23.4 g. of l-phenyl-l-cyclohexylpropaneL'B-diol in 25 m1. of benzene and 31.6 g. of

pyridine was'treated with asolution of21 g. of p-toluenesulfonyl chloride in 50 ml..of benzene, maintaining the.

temperature between 10 and 20 with cooling water.

had been completed, and was thenextracted twice with cold water which had been acidified with enough hydrochloric acid to react with .substantially all of the pyridine used. The benzene layer was then extracted with 15% temperature of 30-40 for 7 days.

aqueous sodium bicarbonate solution. Removal of the solVentfrom the benzene solution by vacuum distillation, using steam heat, left 36 g. of residue. This was caused. to crystallize by the addition of a pentane fraction. of petroleum ether, and melted at -945". The product was recrystallized from a benzene pentane mixture and' then melted with decomposition about 92, after preliminary softening about 84 EXAMPLE 5 v N-methyl-fi-phenyl-fl-cyclohexyl-fl-11ydroxypropionamide 27.5 g. of ethyl fi-phenyl-B-cyclohexyl-B-hydroxypropionate', 6.45- gJOfmethyIamine and ml. of methanol were placed in. a tightly stoppered flask and kept at a The solvents were distilled ofl under reduced pressure and the residue dissolved in- 50 mli warm methanol. Water was added to turbidityand the solution was allowed to cool slowly. On" filtration,2-5.7 g. of the crystalline amidewas 'ob-i tained, meltinglOZ-lOS. Recrystallization from nitromethane gave material melting 114-1 16.

' 0 EXAMPLE 6 I-phenyl-I-cyclohexyl-1-hydr0xy-3-methylaminopropane In a carefully driedl liter, 3 necked flask with stirrer, condenser and dropping funnel was put 4.32 g. LiAlI-I, and ml. absolute ether. To this was added a suspension of 19.67. g. of N-methyl-(3-phenyl-B-cyclohexyl-flhydroxypropionamide in 300 ml. of absolute ether, at a A rate sufficient to maintain gentle refluxing. The mixture was refluxed 4% hours, then cooled and water was added cautiously to decompose the excess LiAlH j. A saturated aqueous solution of 9 g. of ammonium chloride was added dropwisewithstirring and the ether layer was decanted. A

theoretical amount of unreaeted starting amide, which could then be recycled.

EXAMPLE 7 N- (3-phenyl-3-cycl0hexyl 3-hydr0xypropyl-) -N-methyl pyrollidinium-p-toluenesulfonate In a vial were placed 680 mg. of 3-phenyl-3-cyclohexyl-3-hydroxypropyl-3-p-toluenesulfonate, 220 mg. of N-methylpyrrollidine, and ml. of toluene. The mixture was stoppered and heated at 50 for four days, and at 95 for an additional 2 /2 days. Removal of the toluene by vacuum distillation left an oil which soon crystallized and could be recrystallized from absolute ethanol and ether, M. P. 168.5-169.5. It was identical in chemical and biological properties to a sample obtained by another route.

EXAMPLE 8 N (3-ph enyl-3-cycl0hexyl-3-hydroxypropyl -triethylammonium p-toluenesulfonate A mixture of 3.89 g. of 3-phenyl-3-cyclohexyl-3-hydropropyl p-toluenesulfonate, 2.02 g. of triethylamine, ml. of absolute ethanol, and a few milligrams of phenol was heated in a sealed pressure-resistant bottle on a steam bath for 3 days. The solvent and excess amine were then removed by distillation on the steam bath at 20-50 mm. pressure. The remaining viscous oil was dissolved by the addition of a small amount of absolute ethanol, and absolute ether was added to faint turbidity. The addition of a crystal of the product and scratching of the flask caused the product to crystallize.

EXAMPLE 9 Conversion of N-(3-phenyl-3-cyclohexyl-3-hydroxypropyl)-methylamine hydrochloride to N-(3-phenyl-3-cyclohexyl-3-hydroxypropyl) -N-methylpyrrollidinium bromide 6.5 g. of the above named methylamine hydrochloride was converted to the free base by solution in water and addition of somewhat over the theoretical amount of aqueous alkali. The free amine was extracted into 200 ml. of benzene, and the benzene solution was put in a 500 ml. flask. A solution of 5.2 g. of 1,4-dibromobutane in 200 ml. of absolute ethanol was added, and 1.6 g. of anhydrous powdered potassium carbonate. The mixture was heated under reflux for 21 hours, cooled, and benzene was added to make the solution about 80% benzene, to render the inorganic salts insoluble. After filtration, the solution was evaporated to a small volume, brought to approximately the initial solvent composition, and then absolute ether was added to faint turbidity, vigorous scratching caused crystallization of the substituted pyrrollidiniumbromide, M. P. ca. 191-195 in analytically pure condition.

We claim:

1. The method of preparing an hydroxy quaternary ammonium salt represented by the formula:

6 wherein R, R and R" are selected from the class consisting of lower alkyl groups, and R and R, when joined in ring form, are selected from the class consisting of the pyrrollidino and piperidino rings, which comprises condensing a phenyl cycloalkyl ketone with an ester of a haloacetic acid to give an hydroxy ester on CoHsC-OH2C O OAlk eyeloalk reducing this ester to a glycol,

OH COHv-(L-CHaCHzOH cycloalk converting the glycol to a mono ester of a hydrocarbylsulfonic acid and reactingthis compound with a tertiary amine NRR'R".

2. The method of preparing a quaternary ammonium salt of the formula:

0H otnr-ria-omcnr-iw' X- CaHn wherein X" is the anion of a non-toxic acid, which comprises condensing phenylcyclohexylketone with zinc and an ester of bromoacetic acid to give the hydroxy ester,

reducing this ester with lithium aluminum hydride to form the glycol,

OH CcHs-fill-CHrCHzOH OoHn reacting the glycol with p-toluene sulfonyl chloride to make the tosylate, and reacting the tosylate 0H CsHs--CHzOHzOSOzCyEb 01111 with N-methyl pyrrollidine to produce the desired quaternary salt.

References Cited in the file of this patent UNITED STATES PATENTS 2,576,103 Cawley et al Nov. 27, 1951 2,682,543 Adamson et al June 29, 1954 2,698,325 Adamson et a1 Dec. 28, 1954 2,716,121 Denton Aug. 23, 1955 OTHER REFERENCES LiAlH, Bulletin 401A, page 3, Metal Hydrides, Inc., June 27, 1951. 

1. THE METHOD OF PREPARING AN HYDROXY QUATERNARY AMMONIUM SALT REPRESENTED BY THE FORMULA: 